The present invention relates to a method for preparing an aqueous emulsion for use in coating a medicine, in particular, an enteric solid pharmaceutical preparation.
In the solid pharmaceutical preparation provided with an enteric coating, the enteric coating serves to not only protect drugs having low resistance to acids from the attack thereof in the stomach, but also protect the gastric mucous membrane from the attack of drugs which may stimulate and damage the wall of the stomach and is dissolved after the arrival at the intestines in which the pharmaceutical preparation shows its desired pharmacological action. There have been used acrylic polymers and cellulosic polymers as enteric coating bases. The acrylic polymer may be, for instance, a copolymer of methacrylic acid and ethyl acrylate. Examples of such cellulosic polymers are cellulose acetate phthalate, hydroxypropyl-methyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, cellulose acetate trimellitate, and carboxymethylethyl cellulose. These coating bases are used in the coating treatment of pharmaceutical preparations in the form of a solution in an organic solvent or an aqueous latex or an aqueous dispersion.
Ethyl cellulose has widely been used as a coating base for solid pharmaceutical preparations such as tablets and granules. Ethyl cellulose is prepared by reacting linter pulp or wood pulp as a raw material with an etherifying agent. In ethyl cellulose, 45 to 50% of the hydroxyl groups present therein are replaced with ethoxy groups and therefore, ethyl cellulose has hydrophobicity and thus exhibits excellent film-forming properties. Ethyl cellulose has been used in the field of drugs and, more specifically, it is used, as an agent for masking a bitter taste of a drug, in a coating film for sustained release pharmaceutical preparations or the like, while making the most use of properties of these ethoxy groups. When practicing the coating procedures using ethyl cellulose, the cellulose is first dissolved in an organic solvent and then applied to solid pharmaceutical preparations.
Recently, the use of organic solvents has been regulated due to the problem of environmental pollution and accordingly, coating treatments which make use of aqueous systems have widely been adopted.
There have already been proposed a variety of coating techniques which make use of aqueous systems. For instance, Japanese Patent Application Publication No. 60-43334 discloses a coating emulsion of an acrylic polymer. The acrylic polymer is a copolymer obtained through emulsion polymerization of methacrylic acid and ethyl acrylate and stably dispersed in the coating emulsion in the form of particles having a particle size of not more than 1.mu.m. However, the coating emulsion comprises residual emulsifying agent, polymerization initiator, chain transfer agent, unreacted monomers or the like and is not preferred as an ingredient of solid pharmaceutical preparations from the viewpoint of safety.
In addition, there has also been proposed a method for preparing an aqueous coating system which comprises dispersing a cellulosic polymer in water. Examples of methods for dispersing a cellulosic polymer in water include a method comprising adding salts together with the polymer or neutralizing the carboxyl groups of the polymer and a method comprising dispersing, in water, the cellulosic polymer in the form of fine particles thereof.
With regard to the former method, Japanese Patent Application Publication No. 61-56221 discloses a method comprising the steps of emulsifying cellulose acetate phthalate, then adding a phosphoric acid salt as an antiflocculant and spray-drying the resulting emulsion to give a powdery polymer capable of being redispersed in water. The emulsification of cellulose acetate phthalate is carried out according to the method as disclosed in U.S. Pat. No. 4,177,177. Moreover, Japanese Patent Provisional Publication No. 56-30913 discloses a method in which cellulose acetate phthalate or hydroxypropylmethyl cellulose phthalate is used in coating procedures in the form of an aqueous solution of the cellulose derivative neutralized with ammonia. In addition, Japanese Patent Provisional Publication No. 58-135807 discloses a method which comprises the steps of neutralizing a cellulosic polymer with an alkali, then dissolving it in water and adding a carboxylic acid to the resulting solution. All of the films for coating solid enteric pharmaceutical preparations formed according to these methods comprise residual alkali salts or ammonium salts of the carboxylic acids used. For this reason, the quality of the resulting coated solid pharmaceutical preparations would be deteriorated or impaired because of high hygroscopicity of these alkali or ammonium salts remaining in the coating film.
With regard to the latter method, Japanese Patent Application Publication No. 56-12614 discloses a method comprising dispersing a cellulosic polymer having an average particle size of not more than 100 .mu.m in water which comprises a gelling agent (plasticizer) and has a boiling point of not less than 100.degree. C. Moreover, Japanese Patent Application Publication Nos. 57-53329 and 58-55125 disclose that triacetin ortriethyl citrate is used as a gelling agent. When mechanically pulverizing a polymer derivative to disperse the polymer, the particle size of the resulting powdery polymer is at least not less than 1 .mu.m. The use of a plasticizer is indispensable to the dispersion of such a polymer having a particle size of not less than 1.mu.m, the polymer is softened through heating and precipitated in the dispersion through flocculation.
Alternatively, Japanese Patent Provisional Publication No. 63-192725 discloses a method which comprises dispersing ethyl cellulose having an average particle size of not more than 100 .mu.m together with a water-soluble plasticizer to give a sustained release film-forming agent, as a technique for coating solid pharmaceutical preparations.
In these dispersions for use in such a coating treatment, the polymer should have a particle size of at least not less than 1.mu.m since the polymer is mechanically pulverized. In this case, the use of a plasticizer is likewise indispensable to the dispersion of a polymer having a particle size of not less than 1.mu.m, the polymer is softened through heating and precipitated in the dispersion through flocculation. Moreover, the dispersion, i.e., the sustained release film-forming agent, prepared according to this method must be coated in a substantial amount to ensure the formation of a film having sustained release properties.
Japanese Patent Application Publication No. 3-39490 discloses a method for eliminating the drawbacks associated with the coating technique which makes use of the aqueous cellulose system, by reducing the particle size of a cellulosic polymer dispersed in water through emulsification. The emulsification is carried out according to the method as disclosed in U.S. Pat. No. 4,177,177. More specifically, the cellulosic polymer is dissolved in a water-immiscible organic solvent to give a polymer solution. A hydrocarbon having not less than 8 carbon atoms (such as cetyl alcohol) and a surfactant as stabilizers are added to the polymer solution and then the resulting polymer solution is treated by a particular emulsifier such as a high pressure homogenizer to give an emulsion. As has been discussed above in detail, the conventional aqueous coating solutions comprise components other than the cellulosic polymers such as stabilizers and surfactants. These stabilizers and surfactants often impair the resistance to acid and stability of the resulting coated solid pharmaceutical preparations. For this reason, there has been desired for the development of a coating solution having a simple composition as much as possible.